There are many cancers that are difficult to treat and although therapy is available, there appears to exist or to come into existence, a degree of resistance to the therapy. Primary resistance may occur in that cancer does not respond to treatment from the outset. This is may be due to the fact that the therapies used do not target precisely enough and effectively enough the type of cancer at hand. Secondary or acquired resistance also occurs quite frequently, which means that a therapy to which the patient seems to respond initially, at a certain time, loses its efficacy. With chemotherapy, for example overall approximately 80% of patients diagnosed with ovarian epithelial, primary peritoneal cancer will relapse after first-line platinum-based and taxane-based chemotherapy. That is not a very encouraging statistic.
There are numerous reasons for resistance, for example some cancers are discovered at a late stage and/or a simply not responsive to treatment.
Mechanisms by which cancers avoid the therapeutic effect of therapy include but are not limited to:                i) mutations which render the cancer less vulnerable to the treatment (e.g. mutation of the site of action of the therapy),        ii) active transportation of the drug out of the tumor, for example by p-glycolation,        iii) building up physical defences, for example stroma which inhibit certain immune responses, and        iv) certain cancers develop paths to repair damage caused by some anti-cancer therapies.        
Tumor heterogeneity may also contribute to resistance, where small subpopulations of cells may acquire or stochastically already possess some of the features enabling them to emerge under selective drug pressure. This is a problem that many patients with cancer encounter, and it obviously limits the therapeutic alternatives that are effective and worsens the prognosis.
Cancer therapy guidelines describe recommended cancer therapies, which includes recommendations for the order or sequence in which the therapies are employed. Thus if a patients show disease progression on the first therapy (“first line”), then a next therapy (“second line”) is recommended, and so on. These therapy recommendations are based on available scientific data and experience, and illustrate that resistance to one therapy does not exclude that another therapy may be effective. At a late stage cancers do not respond to most therapies and no more avenues of therapy exist. These cancers are completely therapy refractory, unless new therapies can be found which are effective.
Cholangiocarcinoma is a prime example of both primary and secondary resistance and is considered to be an incurable and a rapidly lethal malignancy unless both the primary tumor and any metastases can be fully resected (removed surgically). No curative treatment exists for cholangiocarcinoma except surgery. Unfortunately, most patients have advanced stage disease which is inoperable at the time of diagnosis. Patients with cholangiocarcinoma are generally managed—though never cured—with chemotherapy, radiation therapy, and other palliative care measures. These are also used as adjuvant therapies (i.e. post-surgically) in cases where resection has apparently been successful (or nearly so).
In the Western hemisphere cholangiocarcinoma is a relatively rare neoplasm that is classified as an adenocarcinoma (a cancer that forms glands or secretes significant amounts of mucins). It has an annual incidence rate of 1-2 cases per 100,000 in the Western world. However, rates of cholangiocarcinoma have been rising worldwide over the past several decades. Furthermore, the incidence is higher in Asian countries where it is recognized as a significant problem.
Thus there is a need for improved or alternative cancer therapies to address the unsolved problem of primary and secondary therapy resistance.
(R)—N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(4-methyl-4,5,-dihydro-oxazol-2-yl)-quinazoline-4,6-diamine (Varlitinib Example 52 disclosed in WO2005/016346), is a small-molecule pan-HER inhibitor. It has been tested as a monotherapy in phase I clinical trials of gastric cancer patients. 23 patients, who had previously failed on one or more rounds of chemotherapy, and where eligible for trastuzumab, each received 500 mg of Varlitinib orally twice daily (BID) as monotherapy for 28 days. Tumour biopsies taken before and after treatment were analysed using immunohistochemistry. Signs of clinical activity included downregulation of signalling pathways responsible for cell proliferation, and a reduction in cell survival and cell proliferation in gastric tumours that were either co-expressing EGFR and HER2 or that were HER2 amplified.
Varlitinib has now been employed in combination with several different cytotoxic agents to treat cancer, after primary therapy has failed (either where the first line response became refractory, or wherein cancer did not respond to primary therapy). Some of the patients had previously received several lines of therapy, which had failed, until finally they were given Varlitinib in combination with chemotherapy.
The current experimental clinical data generated shows unexpected therapeutic activity of Varlitinib in particular in combination with cytotoxic agents. In some instances the patients had already received multiple rounds of different therapies including chemotherapy, which had all failed. Thus whilst Varlitinib has shown promising anticancer activity in its own right when Varlitinib is used in combination with chemotherapy, increased efficacy may be observed. This seems to be the case even when the patient was resistant to chemotherapy. Some of these patients show an encouraging “response” to the Varlitinib combination therapy. In several patients the therapy according to the present disclosure has shown a surprising level of efficacy.
The data generated suggests that Varlitinib used in combination with chemotherapy is a way to sensitize the cancer to treatment (either to Varlitinib or to the chemotherapy or both), in particular to treatment with cytotoxic chemotherapy.